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Development of a Novel Method for the Preparation of Thiolated Polyacrylic Acid Nanoparticles

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Abstract

Purpose

To develop a novel method for the preparation of thiolated polyacrylic acid nanoparticles via ionic gelation.

Materials and Methods

In a first step nanoparticles were generated by ionotropic gelation of polyacrylic acid (PAA) of three different molecular weights (100, 240 and 450 kDa) and various cations including Ca2+, Mg2+, Zn2+, Al3+ and Fe3+. Via in vitro characterization of the particles (particle size, size distribution and zeta potential) the optimal preparation conditions were established. Taking into consideration, that thiolated polyacrylic acid (PAA-Cys) displays higher mucoadhesive and permeation enhancing properties than unmodified PAA, PAA-Cys nanoparticles were produced in the same manner with Ca2+, as the most promising results concerning particle size and stability of particles could be achieved with this ionic crosslinker. The nanoparticles were stabilized via the formation of inter- and intrachain disulfide bonds within these particles due to oxidation with H2O2. Ca2+ was removed proximately by the addition of EDTA and exhaustive dialysis.

Results

Using the preparation method described above PAA-Cys nanoparticles of a mean diameter of about 220 nm (PAA100-Cys), 250 nm (PAA240-Cys) and 295 nm (PAA450-Cys) can be generated. In comparison to PAA nanoparticles ionically crosslinked with Ca2+, the removal of the crosslinker Ca2+ from PAA-Cys particles led to a nearly three-fold decrease in the zeta potential, from about −7 up to −20 mV. Apart from this advantage, covalently crosslinked PAA-Cys nanoparticles were more firm as they remained stable when incubated in hydrochloride solution, whereas ionically crosslinked particles dissolved at pH lower than 5.

Conclusions

This novel nanoparticulate delivery system seems to be a promising vehicle for the administration of therapeutic proteins, genes and antigens via mucosal membranes.

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References

  1. A. J. Coupe, S. S. Davis, and I. R. Wilding. Variation in gastrointestinal transit of pharmaceutical dosage forms in healthy subjects. Pharm Res. 8:360–364 (1991).

    Article  PubMed  CAS  Google Scholar 

  2. G. Ponchel and J. Irache. Specific and non-specific bioadhesive particulate systems for oral delivery to the gastrointestinal tract. Adv. Drug Deliv. Rev. 34:191–219 (1998).

    Article  PubMed  CAS  Google Scholar 

  3. T. Kubik, K. Bogunia-Kubik, and M. Sugisaka. Nanotechnology on duty in medical applications. Curr. Pharm. Biotechnol. 6:17–33 (2005).

    PubMed  CAS  Google Scholar 

  4. B. Kriwet, E. Walter, and T. Kissel. Synthesis of bioadhesive poly(acrylic acid) nano- and microparticles using an inverse emulsion polymerization method for the entrapment of hydrophilic drug candidates. J. Control. Release 56:149–158 (1998).

    Article  PubMed  CAS  Google Scholar 

  5. S. Ribeiro, N. Hussain, and A. T. Florence. Release of DNA from dendriplexes encapsulated in PLGA nanoparticles. Int. J. Pharm. 298:354–360 (2005).

    Article  PubMed  CAS  Google Scholar 

  6. S. A. Agnihotri, N. N. Mallikarjuna, and T. M. Aminabhavi. Recent advances on chitosan-based micro- and nanoparticles in drug delivery. J. Control. Release 100:5–28 (2004).

    Article  PubMed  CAS  Google Scholar 

  7. N. A. Peppas and P. A. Buri. Surface interfacial and molecular aspects of polymer bioadhesion on soft tissues. J. Control. Release 2:257–275 (1985).

    Article  CAS  Google Scholar 

  8. D. E. Chickering III and E. Mathiowitz. Definitions, mechanisms, and theories of bioadhesion. Drugs Pharm. Sci. 98:1–10 (1999).

    CAS  Google Scholar 

  9. V. Grabovac, D. Guggi, and A. Bernkop-Schnürch. Comparison of the mucoadhesive properties of various polymers. Adv. Drug Deliv. Rev. 57:1713–1723 (2005).

    Article  PubMed  CAS  Google Scholar 

  10. M. Roldo, M. Hornof, P. Caliceti, and A. Bernkop-Schnürch. Mucoadhesive thiolated chitosans as platforms for oral controlled drug delivery: synthesis and in vitro evaluation. Eur. J. Pharm. Biopharm. 57:115–121 (2004).

    Article  PubMed  CAS  Google Scholar 

  11. V. M. Leitner, D. Guggi, A. H. Krauland, and A. Bernkop-Schnürch. Nasal delivery of human growth hormone: in vitro and in vivo evaluation of a thiomer/glutathione microparticulate delivery system. J. Control. Release 100:87–95 (2004).

    Article  PubMed  CAS  Google Scholar 

  12. M. K. Marschütz and A. Bernkop-Schnürch. Thiolated polymers: self-crosslinking properties of thiolated 450 kDa poly(acrylic acid) and their influence on mucoadhesion. Eur. J. Pharm. Sci. 15:387–394 (2002).

    Article  PubMed  Google Scholar 

  13. A. Bernkop-Schnürch, V. Schwarz, and S. Steininger. Polymers with thiol groups: a new generation of mucoadhesive polymers? Pharm Res. 16:876–881 (1999).

    Article  PubMed  Google Scholar 

  14. A. F. Habeeb. A sensitive method for localization of disulfide containing peptides in column effluents. Anal. Biochem. 56:60–65 (1973).

    Article  PubMed  CAS  Google Scholar 

  15. C. E. Kast and A. Bernkop-Schnürch. Thiolated polymers: development and in vitro evaluation of chitosan-thioglycolic acid conjugates. Biomaterials 22:2345–2352 (2001).

    Article  PubMed  CAS  Google Scholar 

  16. A. Bernkop-Schnürch and M. E. Krajicek. Mucoadhesive polymers as platforms for peroral peptide delivery and absorption: synthesis and evaluation of different chitosan-EDTA conjugates. J. Control. Release 50:215–223 (1998).

    Article  PubMed  Google Scholar 

  17. T. K. De, D. J. Rodman, B. A. Holm, P. N. Prasad, and E. J. Bergey. Brimonidine formulation in polyacrylic acid nanoparticles for ophthalmic delivery. J. Microencapsul. 20:361–374 (2003).

    Article  PubMed  CAS  Google Scholar 

  18. B. Kriwet, E. Walter, and T. Kissel. Synthesis of bioadhesive poly(acrylic acid) nano- and microparticles using an inverse emulsion polymerization method for the entrapment of hydrophilic drug candidates. J. Control. Release 56:149–158 (1998).

    Article  PubMed  CAS  Google Scholar 

  19. P. Calvo, C. Remunáz-López, J. L. Vila-Jato, and M. J. Alonso. Novel hydrophilic chitosan-polyethylene oxide nanoparticles as protein carriers. J. Appl. Polym. Sci. 63:125–132 (1997).

    Article  CAS  Google Scholar 

  20. M. Rajaonarivony, C. Vauthier, G. Couarraze, F. Puisieux, and P. Couvreur. Development of a new drug carrier made from alginate. J. Pharm. Sci. 82:912–917 (1993).

    Article  PubMed  CAS  Google Scholar 

  21. K. L. Douglas and M. Tabrizian. Effect of experimental parameters on the formation of alginate–chitosan nanoparticles and evaluation of their potential application as DNA carrier. J. Biomater. Sci. Polym. Ed. 16:43–56 (2005).

    Article  PubMed  CAS  Google Scholar 

  22. T. K. Bronich, P. A. Keifer, L. S. Shlyakhtenko, and A. V. Kabanov. Polymer micelle with cross-linked ionic core. J. Am. Chem. Soc. 127:8236–8237 (2005).

    Article  PubMed  CAS  Google Scholar 

  23. A. E. Clausen and A. Bernkop-Schürch. In vitro evaluation of the permeation-enhancing effect of thiolated polycarbophil. J. Pharm. Sci. 89:1253–1261 (2000).

    Article  PubMed  CAS  Google Scholar 

  24. A. Bernkop-Schnürch, H. Zarti, and G. F. Walker. Thiolation of polycarbophil enhances its inhibition of soluble and intestinal brush border membrane bound aminopeptidase N. J. Pharm. Sci. 90:1907–1914 (2001).

    Article  PubMed  Google Scholar 

  25. A. Bernkop-Schnürch and S. Thaler. Polycarbophil–cysteine conjugates as platforms for oral (poly)peptide delivery systems. J. Pharm. Sci. 89:901–909 (2000).

    Article  PubMed  Google Scholar 

  26. A. Bernkop-Schnürch, A. Weithaler, K. Albrecht, and A. Greimel. Thiomers: Preparation and in vitro evaluation of a mucoadhesive nanoparticulate drug delivery system. Int. J. Pharm. 317:76–81 (2006).

    Article  PubMed  Google Scholar 

  27. K. Albrecht, E. J. Zirm, W. Schlocker, and A. Bernkop-Schnürch. Preparation of thiomer particles and in vitro evaluation of parameters influencing their mucoadhesive properties. Drug Dev. Ind. Pharm. (In press).

  28. D. Guggi, M. K. Marschütz, and A. Bernkop-Schnürch. Matrix tablets based on thiolated poly(acrylic acid): pH-dependent variation in disintegration and mucoadhesion. Int. J. Pharm. 274:97–105 (2004).

    Article  PubMed  CAS  Google Scholar 

  29. A. Lamprecht, U. Schafer, and C. M. Lehr. Size-dependent bioadhesion of micro- and nanoparticulate carriers to the inflamed colonic mucosa. Pharm Res. 18:788–793 (2001).

    Article  PubMed  CAS  Google Scholar 

  30. P. Younessi, M. R. Avadi, K. Shamimi, A. M. Sadeghi, L. Moezi, E. Nahid, K. Bayati, A. R. Dehpour, and M. Rafiee-Tehrani. Preparation and ex vivo evaluation of TEC as an absorption enhancer for poorly absorbable compounds in colon specific drug delivery. Acta Pharm. 54:339–345 (2004).

    PubMed  CAS  Google Scholar 

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Acknowledgment

This work was supported by a Grant from the Austria Nano Initiative to A. Bernkop-Schnürch.

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Authors and Affiliations

  1. Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 52, Josef-Möller-Haus, 6020, Innsbruck, Austria

    Melanie Greindl & Andreas Bernkop-Schnürch

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  1. Melanie Greindl
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  2. Andreas Bernkop-Schnürch
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Correspondence to Andreas Bernkop-Schnürch.

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Greindl, M., Bernkop-Schnürch, A. Development of a Novel Method for the Preparation of Thiolated Polyacrylic Acid Nanoparticles. Pharm Res 23, 2183–2189 (2006). https://doi.org/10.1007/s11095-006-9087-1

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  • DOI: https://doi.org/10.1007/s11095-006-9087-1

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